I. Field of the Invention
The present invention is related generally to transdermal delivery of ionic agents and, more particularly, to the transdermal delivery of local anesthetic agents directly into repaired incisions and skin wounds for the management of pain by the use of an applied electro-motive force (emf), commonly known as iontophoresis.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908 and has since found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine and dexamethasone. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
Earlier, and some present, iontophoretic devices have been typically constructed of two electrodes attached by adhesive materials to a patient, each connected by a wire to a remote power supply, generally a microprocessor-controlled electrical instrument. More recently, self-contained wearable iontophoretic systems have been developed. These systems are advantageous in that they do not have external wires and are much smaller in size. Examples of such systems can be found in a variety of U.S. patents, including U.S. Pat. Nos. 4,927,408; 5,358,483; 5,458,569; 5,466,217; 5,533,971; 5,605,536; 5,651,768; 5,685,837; 6,421,561; 6,653,014; and 6,745,071. Other examples of wearable systems can be found in patent application publications 2005/0010161; 2005/0015042 and 2004/0267169. These systems are also comprised of two electrodes fixed to patients by means of adhesive materials.
Iontophoretic devices have been used for the delivery of anesthetic agents, in order to create a numbing effect in normal intact skin, to prophylactically minimize pain associated with needlestick insertion or minor surgical procedures. Research has demonstrated that this can be an effective treatment, as exemplified, for example, in a research article by Russo et al. (Lidocaine Anesthesia: Comparison of Iontophoresis, Injection, and Swabbing, Am. J. Hosp Pharm, 1980, 37:843-847). The Russo article concludes that iontophoresis of lidocaine through intact skin as a prophylactic treatment for skin anesthesia, is more effective than topical delivery. A commercially available product for this purpose is Numby Stuff®, sold by Iomed Inc. A similar product, LidoSite® is sold by Vyteris, Inc.
These prior art devices are limited to prophylactic treatment of intact skin, using a short application duration of approximately 10-20 minutes, and current levels averaging at approximately 2-4 mA, to achieve sufficient delivery of anesthetic agent to numb skin in areas of approximately 7-8 cm2 (i.e., using current densities of 250-600 microamps/cm2). Ironically, these higher current levels can themselves serve to cause pain that is intended to be avoided.
The efficiency in which ions are transferred into the body by iontophoresis is much lower than 100%, and is dependent on several factors. For best efficiency, the species to be delivered will carry a charge, so that it will flow in the electric field. Also important for maximum efficiency is to minimize competing ions, which are ions of similar charge to the species desired to be transferred. Competing ions present along with the desired delivery species will lower delivery efficiency, by a proportion related to the relative concentration and size of the competing ions. Also serving to reduce delivery efficiency is ions of opposite charge present in the body, which transfer back to the delivery chamber as a proportion of total charge flow. These efficiency effects are known in the art and published in articles such as Phipps et al, Iontophoretic Delivery of Model Inorganic and Drug Ions, J. Pharm Sci., Vol. 78, No. 5, May 1989, pp 365-369. Even under optimal conditions, delivery efficiency is less than 50%. For positively charged drugs of molecular weight 181-260 daltons, efficiency can be 4.2-23.9%. When there is poor efficiency, current levels must be very high to sustain the desired delivery rate. This is problematic in that high current rates are associated with skin damage.
Traditionally, skin wounds and surgically repaired incisions have been treated with oral medication, and/or localized injections. Limitations associated with oral medications include the stomach discomfort associated with NSAIDS, a non-constant pain management owing to the “ups and downs” of blood levels after oral ingestions, and the dangers of addition and respiratory depression associated with narcotics. Limitations associated with local injections of anesthetic agents include the pain associated with the injection itself, as well as a short duration of action related with the eventual migration of medication away from the treatment site.
Other approaches to treat incision and wound pain for protracted periods include mechanical delivery of anesthetic fluids through implanted catheters. This technique suffers from the costly and invasive nature of using implantable catheters. Another approach is to utilize topically applied passive patches, as described in U.S. Pat. Nos. 6,383,511 and 6,645,521. This approach suffers from a slow onset of action related to passive delivery.
Little is known about iontophoretic delivery into wounds, particularly fresh wounds where blood or interstitial fluid will weep into the iontophoretic delivery chamber. These fluids will carry both competing ions of like charge into the delivery chamber, and counter ions of opposite charge. Both serve to interfere with and significantly affect delivery efficiency in an adverse manner. Thus, either much higher current levels would be necessary to overcome the affects of competing ions, or effective delivery may not be possible at all.
As indicated, an example of prior art current and current density with regard to intact skin can be derived from the published study by Russo et al (above). In this article, a charge dosage of approximately 4 mA min per square cm provided a skin anesthesia which lasted approximately 25 minutes in a skin area of 7 cm2. Therefore, this art would suggest that 0.16 mA per sq. cm would be sufficient at a constant rate over intact skin. Therefore, it would be expected that a wound care delivery system would require a much greater current density given an unrestricted path for back-flow of counter ions, which would dominate the total current flow. Thus, because of the interference of competing ions and increased sensitivity to current levels associated with injured skin, direct application of ionic agents should not be a viable approach.
To date, no commercial iontophoretic products exist for sustained delivery of anesthetic agents in order to manage pain following an injury such as a skin wound or surgically repaired incision. U.S. Pat. No. 6,560,483 describes an iontophoretic delivery patch for the sustained treatment of an epidermal target site in the form of a border portion patch that surrounds an aperture region which may contain an incision or skin wound. No contact occurs between the delivery patch and skin at the site of the incision or wound. The effectiveness of that device depends on the lateral movement of medication to the open aperture region, where an incision or skin wound may exist, otherwise the site of pain itself is not treated directly. The limitations of this approach include: a high delivery current that would be required to supply enough medication to treat laterally adjacent tissue, and a relatively slow onset of action associated with the time it takes for a lateral transfer of medication to take place. As mentioned previously, the use of high currents is undesirable as skin damage may occur and that can be self-defeating in the administration of pain medications.
Therefore, a need exists for a better means to treat incisions and wounds that is non-invasive, includes sustained release of medication with rapid onset of action and is comfortable to wear.